The cytotoxic T cell repertoire specific for class I allogeneic and xenogeneic determinants was studied. Through the use of radiation bone marrow chimeras, it was demonstrated that responsiveness to Kb mutant determinants was the outcome of unique interactions between both T cell genotype and maturation environment. Through the use of a transgenic mouse model, in which porcine class I genes had been introduced into the germ line of murine cells, it was demonstrated that normal murine T cells expressed a cytotoxic T cell repertoire specific for xenogeneic class I determinants expressed on mouse cells. This repertoire was cross reactive with the alloreactive cytotoxic T cell repertoire. The nature of polymorphism and allelism were re-evaluated in the minor lymphocyte stimulating (MLs) system. Mls determinants are defined by the ability to stimulate primary proliferative T cell responses between major histocompatibility complex (MHC) identical cells. Originally, Mls was described as a single locus system involving at least four polymorphic alleles. Proliferating T cell clones were generated which were specific for Mlsa, Mlsc, or Mlsd. These, in combination with primary proliferative T cell responses, were then employed to analyze the relationship between Mlsa, Mlsc, and Mlsd determinants. It was found that Mlsd cells appear to express the sum of Mlsa and Mlsc determinants. In addition, formal genetic analyses were carried out to identify the relationship between the genes encoding Mlsa, Mlsac, and Mlsd. It was found that Mlsa and Mlsc are encoded by non-allelic and in fact unlinked genes. Moreover, an Mlsd strain expresses independently the products of unlinked Mlsa-like and Mlsc-like genes. Thus, in contrast to previous understanding, the Mls system is composed of the products of at least two unlinked loci, with no evidence for structural polymorphism at either locus at the present time.